Modification of heparan sulfate (HS) expression on cell surfaces and the extracellular matrix (ECM) provides an important pathway for regulation of growth, differentiation, and development of numerous cell types including vascular endothelial and smooth muscle cells. Recent developments in the field suggest, however, that HS-carrying core proteins themselves are directly involved in outside-in signal transduction. In this grant application, we propose to explore these issues in the context of angiogenesis. The proposal is based on our recent demonstration of a complex series of events involved in modulation of syndecan-4 phosphorylation, which in turn plays a crucial role in the regulation of syndecan-4-dependent activation of PKC-alpha. In addition, we have isolated and identified 2 new proteins for this project that is focused on elucidation of the molecular events involved in syndecan-4- mediated signaling in endothelial cells. The specific aims of this study include: 1) Regulation of syndecan-4 phosphorylation 2) Syndecan- dependent regulation of PKC-a activity; 3) In vivo studies of syndecan-r dependent signal transduction.